Quantitative measurements of daily cholesterol synthesis rates in man are currently performed by procedures that are time-consuming for both the patient and the clinical investigator. They require the existence of the metabolic steady state in which cholesterol input and output are equal and there is no net flux of sterols between body tissues. They are not applicable to rapid determination of the effects of drug/dietary interventions on cholesterol synthesis. The proposed research project is designed to ascertain the clinical applicability of measuring whole body cholesterol synthesis rates in man by analysis of the kinetics of plasma mevalonic acid during constant intravenous infusion of radiolabeled mevalonate. This procedure would be based on indirect measurement in man of the activity of the rate-limiting regulatory enzyme of cholesterol biosynthesis 3-hydroxy-3-methylglutaryl coenzyme A reductase. Kinetic parameters of the measurement and comparisons with the established sterol balance method of determining cholesterol synthetic rates will be performed in rats and in non-human primates in order to define the system and to validate the assumptions inherent in the kinetic measurements of a metabolic process. In addition, the use of animal model systems will allow the determination of the test's applicability to non-steady state conditions. Our ultimate goal is to compare the mevalonate kinetic procedure for measurement of daily sterol synthesis with sterol balance measurements of synthesis rates carried out simultaneously in patients under metabolic ward conditions. If these comparative studies in man and in animal models validate the accuracy of the method, it would then become possible to determine cholesterol biosynthetic rates in man in a one-day procedure that would be applicable to non-steady state conditions. This would allow us to measure the effectiveness of dietary and/or drug interventions in individual patients on the broad scale needed for controlled trials of the Lipid Hypothesis in the free-living population.